Striatal neuronal loss or dysfunction and choline rise in children with attention-deficit hyperactivity disorder: a 1H-magnetic resonance spectroscopy study.
ABSTRACT Twelve previously untreated boys suffering from attention-deficit hyperactivity disorder (ADHD) were investigated by using proton magnetic resonance spectroscopy (1H MRS) before and after one dose (10 mg) of methylphenidate. Pre- and post-methylphenidate spectra were acquired bilaterally in the globus pallidus. Peaks of N-acetylaspartate (NAA), choline (Cho), myo-inositol, glutamate and creatine (Cr) were measured and the ratios of the peaks were calculated and compared with data from ten matched controls. In children having ADHD, NAA/Cr ratio decreased significantly in the bilateral striatum while Cho/Cr ratio showed a mild unilateral increase. One oral dose of methylphenidate did not affect the ratios significantly. These findings suggest that the striatum was bilaterally involved in pediatric ADHD patients. Approximately 20-25% of neurons may have died or may be severely dysfunctional. There seems to be a mild hyperactivity of the cholinergic system.
- [Show abstract] [Hide abstract]
ABSTRACT: Attention-deficit hyperactivity disorder (ADHD) is a heterogeneous psychiatric disorder affecting 5–10% of children. One of the suggested mechanisms underlying the pathophysiology of ADHD is insufficient energy supply to neurons. Here, we investigated the role of omega 3 fatty acids in altering neural energy metabolism and behavior of spontaneously hypertensive rats (SHR), which is an animal model of ADHD. To this end, we employed Proton Magnetic Resonance Spectroscopy (1H MRS) to evaluate changes in brain neurochemistry in the SHR following consumption of one of three experimental diets (starting PND 21): fish oil enriched (FOE), regular (RD) and animal fat enriched (AFE) diet. Behavioral tests were performed to evaluate differences in locomotor activity and risk-taking behavior (starting PND 44). Comparison of frontal lobe metabolites showed that increased amounts of omega 3 fatty acids decreased total Creatine levels (tCr), but did not change Glutamate (Glu), total N-Acetylaspartate (tNAA), Lactate (Lac), Choline (Cho) or Inositol (Ino) levels. Although behavior was not significantly affected by different diets, significant correlations were observed between brain metabolites and behavior in the open field and elevated plus maze. SHR with higher levels of brain tCr and Glu exhibited greater hyperactivity in a familiar environment. On the other hand, risk-taking exploration of the elevated plus maze's open arms correlated negatively with forebrain tNAA and Lac levels. These findings support the possible alteration in energy metabolites in ADHD, correlating with hyperactivity in the animal model. The data also suggest that omega 3 fatty acids alter brain energy and phospholipid metabolism.Behavioural Brain Research 08/2014; 270:240–247. · 3.33 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Abstract Objective: The purpose of this study was to investigate the association between the metabotropic glutamate receptor subtype 7 (mGluR7) gene (GRM7) polymorphism and treatment response to methylphenidate in Korean children with attention-deficit/hyperactivity disorder (ADHD). Methods: We enrolled 175 medication-naïve children with ADHD in an open-label 8 week trial of methylphenidate. The participants were genotyped and evaluated using the Clinical Global Impressions (CGI) Scale and the parent version of the ADHD Rating Scale-IV (ADHD-RS) before and after treatment. Results: After the 8 week course of methylphenidate, children with the GRM7 rs37952452 polymorphism G/A genotype had a more pronounced response rate to the treatment than did children with the G/G genotype according to the ADHD-RS scores (72.2% vs. 55.4%, respectively; p=0.011) and the more stringent standard of combined ADHD-RS and CGI-Improvement (CGI-I) scores (50.0% vs. 35.3%, respectively; p=0.044). Conclusions: The present study suggests that the GRM7 rs37952452 polymorphism may play a role in the treatment response to methylphenidate in children with ADHD. Further studies to evaluate the association between glutamate genes and treatment response to methylphenidate in children with ADHD, including a replication of our findings using a control or comparative group in a larger sample, are warranted.Journal of child and adolescent psychopharmacology 05/2014; · 2.59 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Recent pediatric studies have suggested a correlation between decreased amygdala volume and attention deficit and hyperactivity disorder (ADHD) symptoms, including the emotional dysregulation. To investigate the hypothesis that medication treatment of ADHD specifically improves amygdala function, we used (1)H magnetic resonance spectroscopy (MRS) to study the effect of 12 weeks of treatment with daily 20 mg long-acting methylphenidate on the Glu/Cr, NAA/Cr, Cho/Cr, and mI/Cr ratios in the amygdala of medication-naïve children with ADHD.08/2014; 12(2):137-41.
Striatal neuronal loss or dysfunction and choline rise in children
with attention-deficit hyperactivity disorder:
a1H-magnetic resonance spectroscopy study
Z. Jina,*, Y.F. Zangb, Y.W. Zenga, L. Zhanga, Y.F. Wangb
aCenter for fMRI and Department of Radiology, Hospital 306, P .O. Box 9720, Beijing 100101, China
bInstitute of Mental Health, Peking University, 100083, Beijing, China
Received 7 August 2001; received in revised form 18 September 2001; accepted 18 September 2001
Twelve previously untreated boys suffering from attention-deficit hyperactivity disorder (ADHD) were investigated by
using proton magnetic resonance spectroscopy (1H MRS) before and after one dose (10 mg) of methylphenidate. Pre-
and post-methylphenidate spectra were acquired bilaterally in the globus pallidus. Peaks of N-acetylaspartate (NAA),
choline (Cho), myo-inositol, glutamate and creatine (Cr) were measured and the ratios of the peaks were calculated and
compared with data from ten matched controls. In children having ADHD, NAA/Cr ratio decreased significantly in the
bilateral striatum while Cho/Cr ratio showed a mild unilateral increase. One oral dose of methylphenidate did not affect
the ratios significantly. These findings suggest that the striatum was bilaterally involved in pediatric ADHD patients.
Approximately 20–25% of neurons may have died or may be severely dysfunctional. There seems to be a mild hyper-
activity of the cholinergic system. q 2001 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Attention-deficit hyperactivity disorder; Children; Magnetic resonance spectroscopy; Striatum; N-acetylaspartate; Choline
Attention-deficit hyperactivity disorder (ADHD) is the
most common developmental disorder of childhood, esti-
mated to affect 3–7% of school-age children. The disorder
is associated with a low educational outcome and increased
risk for antisocial disorders and/or drug abuse in adulthood.
Clinically, it is characterized by inattention, hyperactivity
and impulsivity [3,8].
The pathogenic mechanisms of ADHD remain unknown.
Published data have generally implicated frontostriatal
network abnormalities as the likely cause. Previous struc-
tural and functional brain studies in patients with ADHD
have reported reduced volume [2,4,5,9,14], low metabolism
of cerebral glucose  and functional deficit  for
several brain regions, including the frontal lobe, basal gang-
lia, corpus callosum and cerebellum. Involvement of the
dopaminergic system has been suggested since the symp-
toms can be successfully treated with methylphenidate, a
potent blocker of the dopamine transporter. Increased stria-
tal dopamine transporter in adult patients has been
confirmed by a study using single photon emission
computed tomography .
Proton magnetic resonance spectroscopy (1H MRS)
permits reliable non-invasive detection of intracerebral
neurochemical concentrations in vivo. N-acetyl-aspartate
ing the amount and functional state of neurons in a brain
region of interest [6,16]. A low level of NAA is considered
an indicator forneuronal loss orsevere neuronal dysfunction
. In a recently published
concentration was found in five adult ADHD patients .
To the best of our knowledge,
ADHD patients has not yet been published.
The purpose of this study was to determine whether: (1)
there will be any neuronal loss, dysfunction or neurochem-
ical alterations in the striatum associated with structural
abnormalities in children with ADHD; and (2) the above-
mentioned alterations could be affected by methylphenidate
(Ritalin), the drug commonly used in the treatment of
Twelve right-handed male adolescents aged 10–16 years
(mean ¼ 13 years) who presented to the Mental Health
Institute, Peking University, and met the DSM-IV criteria
1H MRS study, reduced NAA
1H MRS data of pediatric
Neuroscience Letters 315 (2001) 45–48
0304-3940/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved.
* Corresponding author. Tel.: 186-10-64871754; fax: 186-10-
E-mail address: firstname.lastname@example.org (Z. Jin).
for ADHD (American Psychiatric Association, 1994) parti-
cipated in the study. No subject had ever been treated with
any drug for ADHD. They received two1H MRS scans. One
scan was performed when the children were drug-naive,
while the other scan was performed 1 or 2 weeks later,
1.5–2 h after one oral dose (10 mg) of methylphenidate.
The control subjects were ten right-handed healthy boys
aged 11–15 years (mean ¼ 13 years). Subject matching was
based on age, gender, handedness and IQ. The control group
received only one1H MRS scan. The exclusion criteria for
all subjects were the presence of: (1) any other psychiatric
disorder and/or neurological disease; and (2) an estimated
full-scale IQ , 80.
This study began in June 2000 and ended in March 2001.
All subjects were male native Chinese children. Informed
consent was obtained from the parents according to guide-
lines of a Local Committee on Human Subjects. All subjects
knew that they would be paid for their participation.
Volume selective1H MRS was performed at the Center
for fMRI, Hospital 306, using a 1.9 T Prestige Imaging/
MRS scanner (Elscint/GE, Haifa) with a circularly polarized
head coil. Standard spin echo T1 and fast spin echo T2
weighted axial images covering the whole brain were
acquired first to guide the MRS localization and screen
Z. Jin et al. / Neuroscience Letters 315 (2001) 45–48
Fig. 1. Axial fast-spin echo T2 weighted image shows the struc-
ture of the basal ganglia and localizer for this1H MRS study.
Fig.2.1Hspectralpeaksof a13-year-oldhealthyboy(on theleft) andan11-year-oldADHD boy(onthe right).Showingthat the amplitude
(height of the peak) of NAA at 2.0 ppm is reduced and the amplitude of choline peak at 3.2 ppm is increased in the ADHD boy as
compared with that of the healthy control.
brain pathology. The single spectral volume of interest was
2 £ 2 £ 2 cm3, which was localized in the globus pallidus
with a random right/left order (Fig. 1). PRESS scan
sequence (TR ¼ 1500 ms; TE ¼ 35.5 ms; NEX ¼ 200;
Matrix ¼ 1020) was used for spectral acquisition. Carefully
shimming for the magnetic field and chemical-shift selec-
tive water suppression scan were completed before the spec-
1H spectra were analyzed online using the software
provided by Elscint/GE. The prominent NAA peak at 2.0
ppm was used as an internal chemical shift reference. The
spectra exhibited peaks of choline complex (Cho) at 3.2
ppm, creatine (Cr) at 3.02 ppm, myo-inositol (mI) at 3.2
ppm, and glutamate plus glutamine (a-Glx) at 3.75 ppm.
For relative quantification of the metabolites, both the area
under the spectral peaks and the amplitude of the peaks were
measured. The measurements were given as peak-area and
peak-amplitude ratios of NAA, Cho, mI, and a-Glx to Cr,
because the peak of Cr at 3.02 ppm is an accepted internal
amplitude reference  (Fig. 2).
Statistical analysis was performed using Staview 5.0 soft-
ware (Abacus Concepts, Berkeley, CA). One-way ANOVA
and post-hoc Bonferroni tests were carried out to detect the
difference of the peak-area and peak-amplitude ratios of
NAA, Cho, mI, and a-Glx to Cr among groups, namely
untreated ADHD children, the same ADHD children after
one dose of 10 mg methylphenidate, and healthy controls. A
P-level of 0.05 was used as the criterion of statistical signif-
The calculated ratios of peak-amplitude and of peak-area
were consistent. Therefore, only the ratios of peak-area
measurements are listed in Table 1.
The NAA/Cr ratios in ADHD children were significantly
decreased with reference to the control values from healthy
children both before and after methylphenidate administra-
tion. Before methylphenidate administration, the mean
NAA/Cr ratio in ADHD children was 28% lower than the
value from healthy controls in the left globus pallidus
(P , 0:0001),and 21% lower
(P , 0:0004). After one oral dose (10 mg) of methylpheni-
date, NAA/Cr ratios remained almost unchanged (about 5%
higher than the value before methylphenidate; P . 0:05).
In ADHD children before methylphenidate administra-
tion, the mean Cho/Cr ratio on the right globus pallidus
was slightly higher than the control value from healthy chil-
dren,i.e.111%ofcontrolvalue(P , 0:05),whiletherewasa
similar but not significant trend on the left side, i.e. 107% of
control value from healthy children (P . 0:05). After one
bilaterally. On the right globus pallidus, Cho/Cr ratio fell
from 111% to 107%, a level not significantly different from
ratio decreased from 107% to 99% of control value from
healthy children. In comparison with the value of Cho/Cr
ratios before and after methylphenidate administration, no
significant difference was found (P . 0:05).
As for the ratios of mI/Cr and a-Glx/Cr, we did not find
significant differences between ADHD patients and healthy
To observe the naive states of ADHD, only the previously
untreated (i.e. having never been treated by any drug for
ADHD) pediatric patients have been included in this
study. The significantly decreased NAA/Cr ratio in globus
pallidus indicates that approximately 20% to 25% of
neurons had died or were severely dysfunctional. These
findings are generally consistent with the
in five adult ADHD patients, which investigated the left
prefrontal cortex and left striatum .
Previously, structural studies have reported unsymmetri-
cal volume abnormalities of the striatum in ADHD patients
[2,13,14]. Our1H MRS data is complementary to the volu-
metric structural studies. In agreement with the structural
MRI findings , we also found that the NAA/Cr ratio is
more significantly decreased on the left side of striatum.
Methylphenidate is the most common drug for the treat-
ment for ADHD. In the present study, a dose of 10 mg was
given to observe the initial response in the previously
1H MRS study
Z. Jin et al. / Neuroscience Letters 315 (2001) 45–48
Peak-area ratios of NAA, Cho, mI and a-Glx to Cr in ADHD chil-
dren and healthy controlsa
MeanStd. Dev. Std. Err.P-value (v.s. control)
aPre-R, in the right striatum of untreated ADHD children; Pre-L,
in the left striatum of untreated ADHD children; Post-R, in the
right striatum of ADHD children after 10 mg methylphenidate;
Post-L, in the left striatum of ADHD children after 10 mg methyl-
phenidate; C-R, in the right striatum of healthy children; C-L, in
the left striatum of healthy children.
untreated children. Surprisingly, no significant improve-
ment could be found after the drug intake. Only about a
5% rise of NAA/Cr ratio had been observed.
Previously, increased Cho/Cr ratio had been reported in
patients suffering from Parkinson’s disease, schizophrenia,
or epilepsy [1,10]. In the present study on ADHD children,
we found a mild unilateral rise of the Cho/Cr ratio in the
striatum. Due to the complex dysregulation of the dopami-
nergic neurotransmitter system in ADHD , an imbal-
ance between the dopaminergic and cholinergic systems
might occur and result in a slightly increased Cho/Cr ratio.
We conclude that in children suffering from ADHD, the
striatum was bilaterally involved. As revealed by the NAA/
Cr ratio, approximately 20–25% neurons in the globus palli-
dus may have died or may be severely dysfunctional. One
oral dose of methylphenidate (10 mg) did not affect the
ratios significantly. There seems to be a mild relative hyper-
activity of the cholinergic system in the striatum.
This study was supported by a grant of National
“Pandeng” Project (95-special-09).
 Aotsuka, A., Shinotoh, H. and Hattori, T., Magnetic reso-
nance spectroscopy in Parkinson’s disease and multiple
system atrophy, Nippon Rinsho, 55 (1997) 249–254.
 Aylward, E.H., Reiss, A.L., Reader, M.J., Singer, H.S.,
Brown, J.E. and Denckla, M.B., Basal ganglia volumes in
children with attention deficit-hyperactivity disorder, J.
Child. Neurol., 11 (1996) 112–115.
 Barkley, R.A., Behavioral inhibition, sustained attention,
and executive functions: Constructing a unifying theory of
ADHD, Psychol. Bull., 121 (1997) 65–94.
 Baumgardner, T.L., Singer, H.S., Denckla, M.B., Rubin,
M.A., Abrams, M.T., Colli, M.J. and Reiss, A.L., Corpus
syndrome and attention-deficit hyperactivity disorder,
Neurology, 4 (1996) 477–482.
 Berquin, P.C., Giedd, J.N., Jacobsen, L.K., Hamburger, S.D.,
Krain, A.L., Rapoport, J.L. and Castellanos, F.X., Cerebel-
lum in attention-deficit hyperactivity disorder: a morpho-
metric MRI study, Neurology, 50 (1998) 1087–1093.
 Danielsen, E.R. and Ross, B., Magnetic Resonance Spectro-
scopy Diagnosis of Neurological Diseases, Marcel Dekker,
Inc, New York, NY, 1999, pp. 11–22.
 Dautry, C., Early N-ace depletion is a marker of neuronal
dysfunction in rats and primates chronically treated with
the mitochondrial toxin 3-nitropropionic acid, J. Cereb.
Blood. Flow Metab., 20 (2000) 789–799.
 Faraone, S.V., Biederman, J., Spencer, T., Seidman, L.J.,
Mick, E. and Doyle, A.E., Attention-deficit/hyperactivity
disorder in adults: an overview, Biol. Psychiatry, 48 (2000)
 Filipek,P.A., Semrud-Clikeman,
Renshaw, P.F., Kennedy, D.N. and Biederman, J., Volu-
metric MR analysis comparing subjects having attention-
deficit hyperactivity disorder and normal controls, Neurol-
ogy, 48 (1997) 589–601.
 Fujimoto, T., Nakano, T., Takano, T., Takeuchi, K., Yamada,
K., Fukuzako, T. and Akimoto, H., Proton magnetic reso-
nance spectroscopy of basal ganglia in chronic schizophre-
nia, Biol. Psychiatry, 40 (1996) 14–18.
 Hesslinger, B., Thiel, T., Tebartz van Elst, L., Hennig, J. and
Ebert, D., Attention-deficit disorder in adults with or with-
out hyperactivity: where is the difference? A study in
humans using short echo1H-magnetic resonance spectro-
scopy, Neurosci. Lett., 304 (2001) 117–119.
 Krause, K.H., Dresel, S.H., Krause, J., Kung, H.F. and Tatsch,
K., Increased striatal dopamine transporter in adult patients
with attention deficit hyperactivity disorder: effects of
methylphenidate as measured by single photon emission
computed tomography, Neurosci. Lett., 285 (2000) 107–110.
 Mataro, M., Garcia-Sanchez, C., Junque, C., Estevez-Gonza-
lez, A. and Pujol, J., Magnetic resonance imaging measure-
ment of the caudate nucleus in adolescents with attention-
deficit hyperactivity disorder and its relationship with
Neurol., 54 (1997) 963–968.
 Semrud-Clikeman, M., Steingard, R.J., Filipek, P., Bieder-
man, J., Bekken, K. and Renshaw, P.F., Using MRI to exam-
ine brain-behavior relationship in males with attention
deficit disorder with hyperactivity, J. Am. Acad. Child.
Adolesc. Psychiatry, 39 (2000) 477–484.
 Teicher, M.H., Anderson, C.M.,Polcari,A., Glod,C.A.,Maas,
L.G. and Renshaw, P.F., Functional deficits in basal ganglia
of children with attention-deficit hyperactivity disorder
shown with functional magnetic resonance imaging relaxo-
metry, Nature Med., 6 (2000) 470–473.
 Vermathen, P., Hippocampal structures: Anteroposterio N-
acetylaspartate differences in patients with epilepsy and
control subjects as shown with proton MR spectroscopic
imaging, Radiology, 214 (2000) 403–410.
 Zametkin, A.J., Nordahl, T.E., Gross, M., King, A.C.,
Semple, W.E., Rumsey, J., Hamburger, S. and Cohen,
R.M., Cerebral glucose metabolism in adults with hyperac-
tivity of childrenhood onset, N. Engl. J. Med., 323 (1990)
Z. Jin et al. / Neuroscience Letters 315 (2001) 45–48